All publications cited herein are incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
The renin-angiotensin system (RAS) or the renin-angiotensin-aldosterone system (RAAS) is a hormone system that regulates blood pressure and fluid balance and is activated when there is a drop in blood volume or blood pressure. When the blood volume is low, renin is secreted into the plasma by the juxtaglomerular cells of the kidneys. The plasma renin carries out the conversion of angiotensinogen released by the liver to angiotensin I (Kumar et al., 2010 “11”. Pathologic Basis of Disease (Eighth ed.). Philadelphia: Saunders Elsevier. p. 493. ISBN 978-1-4160-3121-5). Angiotensin I (AngI) is then converted to angiotensin II (AngII) by the angiotensin converting enzyme (ACE) found in the lungs. AngII is a potent vaso-active peptide which causes blood vessels to constrict, resulting in increased blood pressure. AngII also stimulates the secretion of the hormone aldosterone from the adrenal cortex. Aldosterone causes the tubules of the kidneys to increase the reabsorption of sodium and water into the blood. This increases the volume of fluid in the body, which also increases blood pressure.
AngII activates at least two receptors, namely, angiotensin II type 1 (AT1) and angiotensin II type II (AT2). Majority of the effects of AngII, such as vasoconstriction, proteinuria, fibrosis and inflammation are mediated by the AT1 receptor. Hypertension and proteinuria are the most important risk factors for the progression of renal disease. Haemodynamic and non-haemodynamic effects of angiotensin II are critically involved in the development and maintenance of hypertension and proteinuria. Therefore, suppression of angiotensin II formation by angiotensin-converting enzyme (ACE) inhibitors and blockade of AT1 receptor by angiotensin II receptor blockers (ARB) are powerful therapeutic strategies that effectively slow the progression of renal disease by lowering blood pressure and proteinuria (Wenzel et al., J Renin Angiotensin Aldosterone Syst. 2010 March; 11(1):37-41. Epub 2009 Oct. 27; Wenzel U O, Contrib Nephrol 2001; 135:200-11). It has been speculated that the AT2 receptor may exhibit beneficial effects (such as anti-proteinuric, anti-fibrotic and anti-inflammatory) and that the blockade of the AT1 receptor results in increased synthesis of AngII which in turn stimulates the AT2 receptor (Wenzel et al., J Renin Angiotensin Aldosterone Syst. 2010 March; 11(1):37-41. Epub 2009 Oct. 27).
The inventors observed that peptides of ApoB-100 reduce the levels of the AT1 receptor and therefore these peptides serve as therapeutics in kidney diseases.